Azetidine-3-carboxylic acid is known from EP 29265 and a U.S. counterpart thereof, U.S. Pat. No. 4,555,260, as a gametocide.
A known method for preparing the compound, described in EP 125714 and corresponding U.S. Pat. No. 4,560,507, involves catalytic hydrogenolysis of N-benzylazetidine-3-carboxylic acid using molecular hydrogen in the presence of a palladium on charcoal catalyst, in methanol. However, this method cannot be used to hydrogenolyse the azetidine compound at a concentration which is economically attractive and moreover the need to supply hydrogen gas is a disadvantage. Another known method for such a reaction, described in EP 140437 and corresponding U.S. Pat. No. 4,634,554, uses acetic acid instead of methanol. However, this system has drawbacks. Firstly, after removal of the catalyst the acetic acid has to be flashed off. However, it has a high boiling point (118.degree. C. at 76 cm Hg) and a high tenacity towards azetidine-3-carboxylic acid. After flashing off, therefore, further purification is required in order to obtain a product of acceptable purity. Secondly, acetic acid is not completely inert to azetidine-3-carboxylic acid, since some N-acetylazetidine-3-carboxylic acid is formed. The Applicants discovered that the formation of N-acetylazetidine-3-carboxylic acid could be suppressed by using an acetic acid/water (1/1 by volume) solvent system, but that a new disadvantage arose, namely that the speed of hydrogenation was reduced; and when it was attempted to reduce N-benzylazetidine-3-carboxylic acid in water alone using molecular hydrogen and palladium on charcoal as catalyst it was found that the reaction terminated prematurely, because catalyst clogged at the interface between the water and the toluene, and was thus deactivated.
It is known that catalytic hydrogenolysis of a wide range of compounds may be effected in the absence of molecular hydrogen, provided that a compound which serves as a hydrogen donor is present. In relation to the removal of protecting benzyl-type groups cyclohexane and 1,4-cyclohexadiene have been used as hydrogen donors (J. C. S. Perkin I, vol 5,490-1, 1977; J. Org. Chem., vol. 43, No. 21, p. 4194-6, 1977). N,N-dimethylbenzylamine has been reduced to toluene using triethylammonium formate as hydrogen donor but it is reported that the reaction did not appear to be very useful because it was so slow (J. Org. Chem. vol. 45, No. 24, p. 4926-9). In J. Org. Chem., vol. 44, No. 19, p. 3442-5, 1977 there is described a more advantageous method of removing benzyl and benzyloxycarbonyl protecting groups from peptide compounds, by catalytic hydrogenolysis using formic acid as hydrogen donor. For example, the N-benzyl group was removed from N(epsilon)-benzyllysine by treatment with an equal weight of palladium black in 88% formic acid and n-propanol/water, at room temperature, in 81% yield after 10 hours.
In accordance with the prior art the Applicants sought to use formic acid to replace molecular hydrogen, using amounts of catalyst more commensurate with industrial practice. However, their attempts were not successful, hydrogenolysis either not taking or taking place only in low yield.
Further experiments of the Applicants, based on the use of molecular hydrogen, had revealed an ammoniacal solvent system (methanol/ammonia) to be disadvantageous, ring-opened products being formed in substantial amounts, and proving difficult to remove.